Selective nonoperative versus operative management of liver gunshot injuries: a retrospective cohort study.

INTRODUCTION: Experience accumulated over the last decades suggests nonoperative management (NOM) of civilian gunshot liver injuries can be safely applied in selected cases. This study aims to compare the outcomes of selective NOM versus operative management (OM) of patients sustaining gunshot wounds (GSW) to the liver. METHODS: A registry-based retrospective cohort analysis was performed for the period of 2008 to 2016 in a Brazilian trauma referral. Patients aged 16-80 years sustaining civilian GSW to right-sided abdominal quadrants and liver injury were included. Baseline data, vital signs, grade of liver injury, associated injuries, injury severity scores, blood transfusion requirements, liver- and non-liver-related complications, length-of-stay (LOS), and mortality were retrieved from individual registries. RESULTS: A total of 54 patients were eligible for analysis, of which 37 underwent NOM and 17 underwent OM. The median age was 25 years and all were male. No statistically significant differences were observed between groups regarding patients' demographics, injury scores, grade of liver injury and associated lesions. NOM patients tended to sustain higher-grade injuries (86.5% vs 64.7%; p = 0.08), and failure of conservative management was recorded in two (5.4%) cases. The rate of complications was 48% with no between-group statistically significant difference. Blood transfusion requirements were significantly higher in the OM group (58.8% vs 21.6%; p = 0.012). The median LOS was seven days. No deaths were recorded. CONCLUSION: Patients with liver GSW who are haemodynamically stable and without peritonitis are candidates for NOM. In this study, NOM was safe and effective even in high-grade injuries.

Perfusional evaluation of postesophagectomy gastroplasty with a radioisotopic study.

SUMMARY: Anastomotic fistula represents one of the frequent causes of postoperative morbidity and mortality following transhiatal esophageal resections. The main etiological factor is the ischemia of the gastric tube created for digestive transit reconstruction. Evidence suggests that per operative hypoperfusion can be maintained or even impaired after the surgery. Several methods have been employed in an attempt to assess the blood perfusion of the gastric flap, but they all pose limitations. However, there is a chronological relationship between perfusion assessments, which are almost exclusively performed per operatively, and the occurrence of a leak, which commonly appears several days after the surgery. The authors have developed a method of gastric perfusion evaluation by single photon emission computed tomography scintigraphy, which corrects that temporal matter, allowing the estimation of postoperative gastric perfusion. It is noninvasive, low cost, and may be applied by the time frame when most fistulas occur. High correlation between the event fistula and the low radiotracer uptake in the group of studied patients could be demonstrated. A role in the research of perfusion evaluation of different types of esophageal reconstruction is suggested.

Oxidative stress, hepatocellular integrity, and hepatic function after initial reperfusion in human hepatic transplantation.

BACKGROUND: The mechanisms underlying liver graft dysfunction are not completely defined, although much of the injury derives from oxidative stress in organ reperfusion. The antioxidant glutathione in its reduced form (GSH) is an important agent to detoxify oxygen species after reperfusion. However, this effect might be limited by low concentrations at the end of cold storage. The objective of this study was to evaluate GSH and glutathione oxidized (GSSG) hepatic levels pre- and postreperfusion and correlate with hepatocellular injury and liver function in the 5 subsequent days after transplantation. METHODS: Liver biopsies were taken immediately before implant and 2 hours after venous reperfusion in 34 grafts, determining GSH, GSSG levels, and GSSG/GSH ratio. Aminotransferases (ALT, AST) and PT were measured for 5 days. RESULTS: There was a strong decrease in GSH concentration (P <.0001), increase of GSSG levels (P <.01), and increase of the GSSG/GSH ratio (P <.0001). No correlations were found between GSH, GSSG, or GSH/GSSH levels and AST, ALT, and PT. CONCLUSION: Glutathione levels showed significant changes after 2 hours of reperfusion, due to intense oxidative stress. Therapies to replenish GSH should be considered as a protective measure to avoid liver graft dysfunction after transplantation.

Role of hypotension in brain-death associated impairment of liver microcirculation and viability.

Hypotension in brain-dead organ donors is considered a determinant factor of graft viability. The aim of this study was to elucidate the role of hypotension in brain-death associated impairment of hepatic microcirculation and function. Male Sprague-Dawley rats with an intracranial balloon were used. Group I (n = 7) served as sham controls. In group II (n = 7) brain death was induced through inflation of an intracranial balloon. In group III (n = 7) hypotension without brain death was induced by means of pentobarbital. In group II, a steep rise of arterial pressure was followed by a fall to a lower level (P < 0.01, vs. group I). Also in group III arterial pressure was lower (P < 0.01, vs. group I). In group II, bile production was diminished (P < 0.05). Impaired sinusoidal perfusion (P < 0.01) and enhanced leukocyte endothelium interaction (P < 0.05) were documented in hepatic microvasculature. Electron microscopic analysis revealed vacuolization of hepatocytes; these changes were not observed in group III. Brain death induces specific changes of liver microcirculation, function and histomorphology. Independent of associated hypotension, brain death per se impairs donor liver graft quality.

Changes in hepatic microcirculation and histomorphology in brain-dead organ donors: an experimental study in rats.

OBJECTIVE: To assess the effect of brain death on hormonal homeostasis, hepatic microcirculation, and histomorphology in organ donors. DESIGN: Prospective randomised experimental study. SETTING: Institute for Surgical Research, Germany. SUBJECTS: 12 male Sprague-Dawley rats INTERVENTIONS: 6 rats acted as controls, and 6 had brain death induced by inflation of an intracranial balloon. MAIN OUTCOME MEASURES: Mean arterial pressure, serum concentration of antidiuretic hormone (ADH), thyroxine (T4), free-T4, triiodothyronine (T3) and free-T3, bile production, intravital fluorescence microscopy and electron microscopic appearances. RESULTS: After induction of brain death mean arterial pressure rose within 5 minutes followed by significant hypotension (p < 0.01). ADH concentration was reduced (p < 0.01), as was bile production (p < 0.05). There was impaired sinusoidal perfusion and increased interaction between leucocytes and endothelium in the hepatic microvasculature. The electron microscopic analysis showed vacuolisation of hepatocytes. CONCLUSION: Macrohaemodynamics, ADH homeostasis, and the hepatic microcirculation deteriorate after brain death, which leads to histomorphological damage of hepatocytes and compromised liver function.

Hypertonic saline dextran attenuates leukocyte accumulation in the liver after hemorrhagic shock and resuscitation.

BACKGROUND: Hemorrhagic shock and resuscitation triggers a global ischemia/reperfusion phenomenon, in which activated leukocytes are considered strong contributors to the ensuing tissue damage. METHODS: The aim of the study was to investigate the effects of hypertonic saline dextran (HSD) on the early leukocyte/endothelial interactions (intravital fluorescence microscopy) in a rat model of hemorrhagic shock (1 hour at mean arterial pressure of 40 mm Hg). The resuscitation was performed with lactated Ringer's solution (RL, four times shed blood/20 minutes, n = 6), 6% dextran 60 (DEX, 100% shed blood/5 minutes, n = 8), and 7.2% NaCl/10% dextran 60 (HSD, 10% shed blood/2 minutes, n = 8). RESULTS: After 1 hour of resuscitation, shock-induced stasis/adherence of leukocytes was further enhanced with RL (sinusoids 17.6+/-6.9%; venules 33.9+/-8.5%), whereas DEX and HSD attenuated leukocyte stagnation in sinusoids (DEX -7.4+/-6,1%; HSD -14.7+/-2.9%, p<0.01 vs. RL) and leukocyte adherence in postsinusoidal venules (DEX -12.2+/-8.6%, p<0.05 vs. RL; HSD -27+/-7.4%, p<0.01 vs. RL). CONCLUSION: HSD reduced significantly the number of leukocytes accumulated in the liver after resuscitation of hemorrhagic shock, probably due to a combination of mechanisms of both components.

Impact of brain death on hormonal homeostasis and hepatic microcirculation of transplant organ donors.

To elucidate the pathophysiological mechanisms involved in the deterioration of hepatic graft viability in brain-dead organ donors, the impact of brain death on hepatic microcirculation was investigated with respect to hormonal homeostasis and graft viability. Rats were assigned to two groups: group I (n = 6) served as sham controls, and in group II (n = 6), brain death was induced through insufflation of an intracranial balloon. Mean arterial pressure was elevated significantly within 5 min after the induction of brain death and then decreased significantly to below the control value. Urine osmolality was significantly lower and serum osmolality significantly higher than the control values. Antidiuretic hormone level was significantly lower than the control value. Bile secretion also decreased significantly. Furthermore, in group II there were significantly higher numbers of nonperfused sinusoids (15.9% vs 6.2% in group I), and sinusoidal stagnant and postsinusoidal venular adherent leukocytes (53.9/lobule and 258.6/mm2 versus 25.2/lobule and 124.8/mm2 in group I, respectively). In summary, sinusoidal perfusion is compromised after brain death, possibly, in part, through an increased leukocyte activation and accumulation in the hepatic microvasculature, leading to the deterioration of hepatic function.

Effects of the nitric oxide synthase inhibitors N(G)-nitro-L-arginine methyl ester and aminoethyl-isothiourea on the liver microcirculation in rat endotoxemia.

BACKGROUND/METHODS: The question whether nitric oxide protects or impairs organ perfusion during early endotoxemia has not been completely answered. To evaluate the regulative function of nitric oxide on organ microvascular perfusion and leukocyte accumulation during endotoxemia, we studied the influence of a non-selective nitric oxide inhibitor and a preferential inducible nitric oxide synthase inhibitor (respectively, N(G)-nitro-L-arginine methyl ester and aminoethyl-isothiourea) on liver microcirculation (intravital fluorescence microscopy) in a rat model. RESULTS: Two hours after intraportal injection of lipopolysaccharide (5 mg/kg in 10 min) the rats were randomly treated and received a bolus dose of N(G)-nitro-L-arginine methyl ester (10 mg/kg, n = 7), aminoethyl-isothiourea (10 mg/kg, n = 6) or normal saline, (n = 7). After 1 h, N(G)-nitro-L-arginine methyl ester blockade yielded a higher rate of non-perfused sinusoids than normal saline (27 +/- 2% vs 19 +/- 5%, p < 0.05). LPS-induced leukocyte stagnation in sinusoids was further increased (p < 0.05) in all groups after 1 h treatment, but N(G)-nitro-L-arginine methyl ester clearly accentuated leukocyte accumulation in sinusoids as compared to normal saline (69 +/- 19% vs 16 +/- 4%, p < 0.05). Both modalities of nitric oxide blockade elicited a significant enhancement in the number of leukocytes adherent to the postsinusoidal venules in contrast to normal saline (N(G)-nitro-L-arginine methyl ester 48 +/- 17%, aminoethyl-isothiourea 33 +/- 9% vs normal saline 1 +/- 5%, p < 0.05). CONCLUSIONS: We conclude that complete nitric oxide blockade aggravates lipopolysaccharide-induced hepatic microvascular perfusion failure and enhances leukocyte accumulation, in both sinusoids and post-sinusoidal venules. The preferential inducible nitric oxide synthase inhibitor aminoethyl-isothiourea has a moderate negative effect, favoring leukocyte adhesion in postsinusoidal venules, and its usefulness demands further research, especially concerning its late effects.

Effects of hyperoxic ventilation on hemodilution-induced changes in anesthetized dogs.

BACKGROUND: In subjects who have undergone acute preoperative normovolemic hemodilution (ANH), intraoperative hemorrhage is generally treated by immediate return of autologous blood collected during ANH. Simply increasing blood oxygen content by hyperoxic ventilation (HV, inspiratory fraction [FIO2] 1.0) might compensate for the acute anemia, allow further ANH, and delay onset of autologous blood return. STUDY DESIGN AND METHODS: This study 1) evaluated the effects of HV (FIO2 1.0) upon ANH to a hemoglobin (Hb) concentration of 7 g per dL in anesthetized dogs ventilated with room air and 2) compared the effects of subsequent profound ANH (Hb, 3 g/dL) with and without an intravenous perfluorocarbon emulsion (perflubron 60% wt/vol) versus those of autologous red cell transfusion. The results of the entire study are presented in two parts. Organ tissue oxygenation was assessed in skeletal muscle and liver, and systemic oxygenation status was evaluated. Myocardial contractility was deduced from left ventricular pressure-volume relationship. Seven of 22 dogs underwent further hemodilution while breathing 100-percent O2, for a determination of the Hb concentration at which HV-induced effects were abolished. RESULTS: HV completely reversed the ANH-induced increase in cardiac index (4.6 +/- 0.7 vs. 3.8 +/- 0.9 L/min/m2 before and during HV; p < 0.05) and partially reversed the decrease in systemic vascular resistance (1784 +/- 329 vs. 2087 +/- 524 dyn x cm-5 x sec x m-2; p < 0.05). Despite unchanged global O2 delivery, organ tissue oxygenation improved during HV (mixed venous partial pressure of O2: 40 +/- 3 vs. 59 +/- 7 torr; coronary venous pressure of O2: 30 +/- 4 vs. 43 +/- 6 torr; p < 0.05; liver surface: 31 +/- 11 vs. 39 +/- 13 torr; skeletal muscle surface: 30 +/- 14 vs. 41 +/- 22 torr; p < 0.05). This improvement was due to an increased contribution of physically dissolved O2 in plasma to O2 delivery (3.2 +/- 0.2% before HV vs. 14.6 +/- 1% during HV; p < 0.05) and O2 consumption (whole body: 6 +/- 1% vs. 47 +/- 8%, p < 0.05; myocardium: 4.3 +/- 0.9% vs. 31 +/- 6%, p < 0.05). The beneficial effects of HV were lost after an additional volume-compensated exchange of 19 percent of blood volume (Hb, 5.6 g/dL). CONCLUSION: In anesthetized dogs ventilated with room air and hemodiluted to a Hb of 7 g per dL, simple oxygen therapy by HV (FIO2 1.0) rapidly improves tissue oxygenation and permits extended hemodilution to Hb of 5.8 g per dL until the HV-induced effects are lost.

Hemodilution and intravenous perflubron emulsion as an alternative to blood transfusion: effects on tissue oxygenation during profound hemodilution in anesthetized dogs.

BACKGROUND: Intravenously administered perfluorocarbon (PFC) emulsions increase oxygen solubility in plasma. PFC might therefore temporarily replace red cells (RBCs) lost during intraoperative hemorrhage. In patients who have undergone hemodilution, the return of autologous blood may be delayed by the administration of PFC, and autologous RBCs may be saved for transfusion after surgical bleeding is stopped and PFC is cleared by the reticuloendothelial system. STUDY DESIGN AND METHODS: In 22 anesthetized, hemodiluted dogs (hemoglobin [Hb] 7 g/dL) breathing 100-percent O2, an intraoperative volume-compensated blood loss was simulated. The efficacy of three therapeutic regimens in maintaining tissue oxygenation was compared: 1) RBC group (n = 7): maintenance of a Hb > 7 g per dL by transfusion of autologous RBCs; 2) PFC group (n = 7): bolus application of a second-generation PFC emulsion (60% wt/vol perflubron) and further acute normovolemic hemodilution (ANH) to a Hb of 3 g per dL; and 3) control group (n = 7): further ANH alone to a Hb of 3 g per dL. Systemic and myocardial oxygenation status and tissue oxygenation were assessed. RESULTS: Autologous RBCs transfused to maintain a Hb of 7 g per dL preserved hemodynamics and tissue oxygenation during blood loss. In the PFC and control groups, heart rate and cardiac index increased significantly in response to further ANH. Tissue oxygenation was not different in the PFC and the RBC groups. Direct comparison of the PFC and control groups revealed better tissue oxygenation in the PFC group, as reflected by significantly higher mixed venous, coronary venous, and local tissue pO2 on liver and skeletal muscle. CONCLUSION: Bolus intravenous administration of 60-percent (wt/vol) perflubron emulsion and further hemodilution from a Hb of 7 g per dL to one of 3 g per dL were as effective as autologous RBC transfusion in maintaining tissue oxygenation during volume-compensated blood loss designed to mimic surgical bleeding.

Resuscitation with hypertonic saline dextran reduces endothelial cell swelling and improves hepatic microvascular perfusion and function after hemorrhagic shock.

BACKGROUND: Hemorrhagic shock severely compromises hepatic microcirculation and function with tendency to promote hepatic insufficiency and multiple organ failure. MATERIAL AND METHODS: The aim of the study was to evaluate the effects of small volume resuscitation on liver microcirculation (intravital fluorescence microscopy and electron microscopy) and function (arterial ketone body ratio (AKBR) and bile flow), in a rat model of traumatic-hemorrhagic shock. One hour after hemorrhage (MAP 40 mm Hg) the rats were resuscitated with HSD (7.2% NaCl/10% dextran 60, 10% of shed blood/2 min, n = 8); DEX (6% dextran 60, 100% of shed blood/5 min, n = 8); or RL (Ringer lactate, 400% of shed blood/20 min, n = 6). RESULTS: HSD yielded a better recovery of sinusoidal perfusion (17.8 +/- 0.8% nonperfused sinusoids) than DEX (21.8 +/- 0. 7%, P < 0.05) and RL (23.9 +/- 0.9%, P < 0.01). Hemorrhagic shock produced a moderate increase of mean sinusoidal endothelial cell thickness, which was further enhanced by DEX and RL (P < 0.05 vs baseline), whereas HSD reduced the mean endothelial cell thickness toward baseline (P < 0.05 vs DEX and RL). Both AKBR and bile flow were profoundly reduced after 1 h shock. Resuscitation with DEX and RL produced a weak recovery, still remaining at shock level, while HSD infusion allowed a significant improvement of AKBR and bile flow (P < 0.05 vs shock). CONCLUSION: Reduction of mean endothelial cell thickness after HSD is very likely the mechanism for the amelioration of sinusoidal perfusion, resulting in a significant improvement of hepatic energetic status and excretory function.

The nitric oxide donor sodium nitroprusside protects against hepatic microcirculatory dysfunction in early endotoxaemia.

OBJECTIVE: Endotoxin rapidly inhibits the activity of the constitutive endothelial nitric oxide synthase (ecNOS); this precedes the production of NO from inducible NOS (iNOS). This leaves a period in early endotoxaemia with a supposed scarcity of NO. The present study was conducted to examine the effects of external supplementation of NO on liver microcirculation and function. MATERIAL: 13 male Sprague Dawley rats. INTERVENTIONS: The rats underwent laparotomy, and the left liver lobe was exteriorised. All animals were given a bolus dose of endotoxin (LPS) 5 mg/kg intraportally. One group (n = 6) had a continuous infusion of sodium nitroprusside (SNP) 1.4 microg/kg per min started concurrently, the other group (n = 7) was treated with normal saline. The study was terminated after 3 h LPS. MEASUREMENTS AND RESULTS: Intravital microscopy was performed at baseline, at 2 h and 3 h LPS. Hepatic function was assessed by arterial ketone body ratio, acid base values, and bile flow. At baseline 1% of the sinusoids were without perfusion. After 2 h LPS this figure had risen to 9.8+/-1.5% in the SNP group versus 16.9+/-1.4% in the controls (p < 0.05 vs controls). The corresponding values after 3 h LPS were 13.5+/-1.5 versus 19.3+/-1.5% (p < 0.05 vs controls). The leukocyte count in sinusoids and venules had a similar development. Functional parameters were all slightly better preserved in the SNP group, but with no individual significance versus controls. CONCLUSIONS: Infusion of the NO donor SNP in early endotoxaemia attenuates the detrimental effects of LPS on liver microcirculation, most probably by alleviating a relative deficit of NO at the microcirculatory level.

Use of selective and nonselective nitric oxide synthase inhibitors in rat endotoxemia: effects on hepatic morphology and function.

Endotoxin has profound effects on nitric oxide (NO) production, and considerable controversies exist as to whether these alterations are beneficial or deleterious. Increased mortality has been reported from nonselective inhibition of NO synthase. Results from selective inhibition of the inducible isoform (iNOS) appear largely positive. In a model of rat endotoxemia we have compared the early effects on hepatic morphology and function of selective and nonselective NO inhibition. Two hours after endotoxin injection (5 mg/kg intraportally) the rats were treated with either the selective iNOS inhibitor aminoethyl isothiourea (AE-ITU, 10 mg/kg), the nonselective NOS inhibitor NG-nitro-L-arginine methyl ester (L-NAME, 10 mg/kg), or normal saline. The animals were observed for another hour. Using an immunohistochemical method, induction of iNOS was demonstrated in various tissues in all slices examined. No unequivocal benefit from NO inhibition was noted. Electron microscopic examination revealed widespread alterations of liver morphology, without obvious differences between the groups. Liver function, as assessed by ketone body ratio, hepatic venous acid base values, and bile production, was generally more adversely affected after NO inhibition. Even with the iNOS selective inhibitor AE-ITU no benefit was noted. We conclude that during the early phases of endotoxemia therapeutic reduction of NO production has no positive effects on liver function or morphology.

Comparative effects of hypotension due to isoflurane, nitroglycerin, and adenosine on subendocardial microcirculation: observation of the in situ beating swine heart under critical stenosis.

BACKGROUND: Although isoflurane may cause subendocardial hypoperfusion in the presence of coronary stenosis because of its coronary arteriolar dilatory effects, it is not known how the subendocardial microcirculation is affected. The authors examined the effects of isoflurane on poststenotic subendocardial microvessels with coronary stenosis. METHODS: The authors observed subendocardial microvessels in in situ beating swine hearts with or without critical stenosis of the left anterior descending coronary artery (LAD) with a needle-type videomicroscope during isoflurane- (ISO-H), adenosine- (ADE-H), and nitroglycerin- (NTG-H) induced hypotension (mean arterial pressure, 55 mmHg). Regional myocardial function, oxygen balance, and lactate metabolism in the region perfused by the LAD also were determined. RESULTS: In swine with stenosis, there were no differences in heart rate, cardiac output, and LAD blood flow among the three types of hypotension. Regional lactate production and anterior interventricular venous pO2 were similar during ISO-H and NTG-H but higher during ADE-H. With videomicroscopy, about half as many subendocardial microvessels could be visualized during ADE-H as with ISO-H and NTG-H. The average decrease in the systolic diameter of subendocardial microvessels of greater than 100 microm was 9 +/- 6% during ISO-H and 12 +/- 5% during NTG-H, but no consistent phasic diameter changes were observed during ADE-H. In swine without stenosis, a systolic diameter decrease was observed during all three types of hypotension. CONCLUSIONS: These findings suggest that hypotension induced by isoflurane or nitroglycerin preserves phasic diameter changes in subendocardial microvessels in the presence of critical coronary stenosis, whereas that induced by adenosine does not.

The effect of acute normovolemic hemodilution (ANH) on myocardial contractility in anesthetized dogs.

The influence of severe acute normovolemic hemodilution (ANH) on myocardial contractility (MC) was investigated in 14 splenectomized, anesthetized dogs. MC was assessed by the maximum rate of left ventricular pressure increase (LVdp/dt(max)), end-systolic elastance (Ees), and preload recruitable stroke work (PRSW) (conductance catheter, left ventricular pressure-volume relationship). Measurements of myocardial perfusion and oxygenation (radioactive microsphere technique) assured comparability of the model to previously performed studies. Global and regional myocardial blood flow increased significantly upon hemodilution with preference to midmyocardium and subendocardium. This resulted in preservation of both myocardial oxygen delivery and consumption after ANH. Myocardial oxygen extraction as well as coronary venous Po2 were unaffected by ANH, while coronary venous lactate concentration decreased, indicating that myocardial oxygen need was met. LVdp/dt(max) decreased significantly after hemodilution (2278 +/- 577 vs 1884 +/- 381 mm Hg/s, P < 0.01), whereas Ees and PRSW increased significantly (1.76 +/- 0.54 vs 2.15 +/- 0.75 mm Hg/mL, P < 0.05, for Ees and 33 +/- 14 vs 45 +/- 14 mm Hg.mL, P < 0.05, for PRSW). While the decrease of LVdp/dt(max) most likely reflects ANH-induced changes of ventricular pre- and afterload, the increase of Ees and PRSW indicates a true increase of myocardial contractility during ANH in anesthetized dogs.

Effects of carbamazepine or imipramine alone or in association with amphetamine on the fighting time of REM sleep-deprived rats.

The fighting time of REM sleep-deprived rats was measured after both acute and long-term intraperitoneal treatment with carbamazepine (CBZ) or imipramine (IMI) alone or associated with amphetamine. Fighting time was increased by the lower doses of CBZ (5-20 mg/kg) or IMI (0.5-2 mg/kg) administered acutely. At the highest dose tested, CBZ (40 mg/kg) was not significantly different from the control value, and the fighting time observed after 4 mg/kg IMI was less than that observed with 2 mg/kg. Amphetamine (2 mg/kg) alone increased the fighting time and this effect was not modified by association with 5-40 mg/kg CBZ or 0.5-4 mg/kg IMI. Long-term treatment (14 days) with CBZ (20 mg kg-1 day-1) or IMI (2 mg kg-1 day-1) significantly reduced fighting time in contrast to the increase observed with a single acute treatment at the same dose. The fighting time of rats acutely treated with amphetamine (2 mg/kg) was significantly but not completely reduced by previous long-term pretreatment with CBZ, whereas IMI pretreatment had no effect. The differences between the effects of acute and long-term treatment with CBZ cannot be explained by the development of metabolic tolerance, since serum CBZ levels were the same in both situations.